Chiral N-heterocyclic carbene catalyzed annulation of α,β- unsaturated aldehydes with 1,3-dicarbonyls

Article abstract of DOI:10.1039/c1cc12778k

Chiral N-heterocyclic carbene catalyzed annulations of ynals and enals with 1,3-dicarbonyls have been described. The two reactions provided direct and efficient methods for enantioselective synthesis of functionalized dihydropyranones. Comparatively, the reactions starting from ynals were atom-economical; furthermore the reactions of enals demonstrated broader substrate compatibility. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1cc12778k

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COMMUNICATION
Chiral N-heterocyclic carbene catalyzed annulation of a,b-unsaturated
aldehydes with 1,3-dicarbonylsw
Zhi-Qiang Zhu,a Xing-Liang Zheng,b Ning-Fei Jiang,b Xiaolong Wana and Ji-Chang Xiao*a
Received 11th May 2011, Accepted 3rd June 2011
DOI: 10.1039/c1cc12778k
Chiral N-heterocyclic carbene catalyzed annulations of ynals
and enals with 1,3-dicarbonyls have been described. The two
reactions provided direct and efficient methods for enantioselective
synthesis of functionalized dihydropyranones. Comparatively,
the reactions starting from ynals were atom-economical; furthermore
the reactions of enals demonstrated broader substrate compatibility.
Our investigation started with the reaction of 3-phenyl-
propiolaldehyde 1a with ethyl 3-oxobutanoate 2a in the
presence of chiral NHC precursors A-C (Table 1). We found
that most of the selected carbene catalysts exhibited poor
activity under conditions similar to our previous work
(entry 1).5 A careful screening of chiral NHC catalysts
revealed that the annulated product 3a could be obtained in
29% yield and moderate selectivity when C3 was used with the
addition of catalytic amount of NaOAc (67% ee, entry 2).
We have noticed that in Bode’s reports, the NHC-catalyzed
reactions could occur smoothly in the absence of added base.4a,10
Inspired by this, we re-investigated the above annulation
under conditions without added base. It was found that the
reaction proceeded similarly to give 3,4-dihydropyranone 3a
in nearly the same yield but significantly increased enantio-
selectivity (31% yield and 87% ee, entry 3). However, cinnamic
acid was isolated in 30% yield as a byproduct. The formation
of cinnamic acid could be reasonably attributed to the hydro-
lysis of the intermediate a,b-unsaturated acyl azolium.3–7 We
thought that the addition of desiccant might inhibit this side
reaction. To our delight, the addition of 4 A MS improved the
reaction greatly, giving 3a in 73% yield and 95% ee (entry 4).
Extensive studies showed that MgSO4 and silica are not
suitable desiccants for the reaction (entries 5, 6). Simply
increasing the reaction time or the amount of catalyst has
limited influence on the reaction performance (entries 7, 8).
However, reducing the catalyst loading to 5 mol% decreased
the enantiomeric excess dramatically (entry 9). It was found
that the reaction proceeded equally well at room temperature
to afford the desired product in almost the same yield and
enantioselectivity (entries 8 and 10). Longer reaction time
was necessary for completion at room temperature. Further
decrease of the temperature to 0 1C resulted in no reaction
(entry 11). Increasing the ratio of ynal 1a to 1,3-dicarbonyl 2a
further improved the efficiency of the annulation, giving 3a in
The past decade has witnessed a growing interest in the area
of N-heterocyclic carbenes (NHCs) owing to their versatility
in organocatalytic transformations. A great variety of NHC-
catalyzed reactions have been disclosed.1 Those reactions
involving aldehydes are generally thought to proceed via the
nucleophilic Breslow intermediate.2 The Breslow intermediate
generated from a,b-unsaturated ynals undergoes protonation
(Scheme 1, path a) to yield electrophilic a,b-unsaturated acyl
azolium,3–5 which could be also produced by the oxidation
(path b) of the Breslow intermediate derived from a,b-unsaturated
enals.6 Subsequent annulation of a,b-unsaturated acyl
azolium with 1,3-dicarbonyls led to the formation of 3,4-
dihydropyranones.4,5,6b,7
Dihydropyranones are very important intermediates in
organic synthesis. They were widely employed in the synthesis
of g-lactones, substituted benzenoids, pyridones, etc.8
However, efficient methods for their enantioselective syntheses
are still lacking.9 Recently, Bode et al. have developed a chiral
NHC-catalyzed Claisen rearrangement starting from ynals
and kojic acid derivatives.4a Nevertheless, the desired
annulated dihydropyranones were not stable enough to
be isolated. Although chiral N-heterocyclic carbenes have
recently achieved great progress, highly enantioselective
annulations catalyzed by chiral NHC seems to be challenging.
A suitable chiral NHC catalyst system might be the key
to the successful relay of the stereochemical information
of the above acyl azolium. Therefore, we explored chiral
NHC-catalyzed annulation of a,b-unsaturated ynals or enals
with 1,3-dicarbonyls.
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, China.
E-mail: jchxiao@mail.sioc.ac.cn; Fax: (+86) 21-6416 6128
b School of Chemistry and Biological Engineering,
Changsha University of Science and Technology, Changsha 410114,
China
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc12778k
Scheme 1 NHC-catalyzed annulations to dihydropyranones.
c
8670 Chem. Commun., 2011, 47, 8670–8672
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Table 1 Optimization of reaction conditionsa
Table 2 NHC-catalyzed enantioselective annulation of ynals with
1,3-dicarbonylsa
Entry
R
R1, R2
Yieldb (%)
Eec (%)
1
2
3
4
Ph
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OMe
Me, Me
Me, Ph
81 (3a)
67 (3b)
82 (3c)
87 (3d)
77 (3e)
66 (3f)
74 (3g)
49 (3h)
34 (3i)
81 (3j)
71 (3k)
68 (3l)
52 (3m)
71 (3n)
46 (3o)
60 (3p)
98d
92
97
95
96
96
92
94
96
92
94
85
85
95
95
96
4-OMeC6H4
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-FC6H4
2-FC6H4
4-ClC6H4
4-BrC6H4
1-Naphthyl
2-Thienyl
1-Butyl
5
6
7e
8
Entry Cat. (mol%) Additive T/t, 1C/h Yieldb (%) Eec (%)
9
1d
2d
3
4
5
6
7
8
9
10
11
12e
13f
14f
A-C3 (10)
C3 (10)
C3 (10)
C3 (10)
C3 (10)
C3 (10)
C3 (10)
C3 (15)
C3 (5)
C3 (10)
C3 (10)
C3 (10)
C3 (10)
C3 (10)
t-BuOK rt/2
—
29
31
73
33
—
65
71
62
71
—
75
81
31
—
67
87
95
88
—
96
95
58
95
—
96
98
85
10
11
12f
13f
14
15
16f
NaOAc rt/24
— 40/24
4 A MS 40/8
1-c-C6H11
Ph
Ph
MgSO4
Silica
40/24
40/24
4 A MS 40/24
4 A MS 40/8
4 A MS 40/24
4 A MS 40/48
4 A MS 0/24
4 A MS 40/8
4 A MS 40/8
Ph
a
Performed on a 0.2 mmol scale with 1.5 equiv. of 1, 1 equiv. of 2,
10 mol% of C3, and 200 mg of 4 A MS in 0.1 M in toluene at 40 1C for
8 h. Isolated yield after chromatography. Determined by HPLC
b
c
d
analysis on a chiral column. Absolute configuration determined
e
by conversion to (R)-methyl 5-oxo-3-phenylhexanoate. 1 equiv. of
—
40/8
f
aldehyde and 1.5 equiv. of 3-oxobutanoate were used. At room
temperature for 48 h.
a
Performed on a 0.2 mmol scale with 1 equiv. of 1a, 1.2 equiv. of 2a,
200 mg of additives and indicated amounts of catalyst in 0.1 M in
b
toluene. Isolated yield. Determined by HPLC analysis on a chiral
c
d
column. Performed in THF with 10 mol% of additive. 1.2 equiv. of
e
we extended the above investigation to a,b-unsaturated enals.
After simple screening of the catalyst and optimization of
reaction conditions, it was found that the above conditions
were still the best (see ESIw). The only modification was the
addition of quinone oxidant (Table 3). Under this optimal
condition, the reaction could accommodate a variety of enals
and 1,3-dicarbonyls. Both electron-rich and electron-poor aryl
or heteroaryl-substituted enals reacted well with 1,3-dicarbonyls,
giving the desired annulated dihydropyranones in moderate to
good yields (37–90%) and high enantioselectivities (generally
Z 90%) (entries 1–15, 17–22). The electronic properties of the
substituents on the aryl ring had no obvious effect on the
reactivity, which is different from the above reaction with
ynals. In the case of aliphatic-substituted aldehyde, (E)-but-2-enal
(entry 16), the enantioselectivity decreased slightly as compared
with the aryl-substituted ones, which is similar to the reaction
with ynals (Table 2, entries 12, 13).
f
1a and 1 equiv. of 2a were used. 1.5 equiv. of 1a and 1 equiv. of 2a
were used.
81% yield and 98% ee (entries 12, 13). Even with a high ratio of
1a to 2a, the addition of 4 A MS was still necessary for the
success in achieving good yield and enantioselectivity (entry 14).
With the optimised conditions in hand, the scope of the
substrate was investigated (Table 2). High enantioselectivity
was obtained for other aryl-substituted ynals, regardless of the
position and electronic nature of the substituent on the aryl ring
(entries 2–11). However, the yield of the dihydropyranones
was somewhat influenced by the electronic properties of the
substituents. Introduction of electron-withdrawing groups such
as Cl and Br on the aromatic ring decreased the yield greatly
(entries 8, 9). With 3-(4-nitrophenyl)propiolaldehyde, only a
complex mixture was afforded (not shown). However, fluorine
substituents seemed to have no remarkable effect on the
reactivity (entries 6, 7). In the case of aliphatic substituted ynals,
the enantioselectivity was slightly decreased even at room
temperature (entries 12, 13; 85% ee). Other 1,3-dicarbonyl
derivatives such as methyl 3-oxobutanoate and 1,3-diketones
were also applicable to this annulation, giving the desired product
in excellent enantioselectivities (entries 14–16, 95–96% ee). It
should be mentioned that all the above dihydropyranones 3a-p
are rather stable, which is much different from those obtained
from the reaction of ynals with kojic acid derivatives.4a
In summary, we developed two chiral N-heterocyclic carbene
catalyzed annulations of ynals and enals, respectively with
1,3-dicarbonyls, which provide direct and efficient methods for
stereoselective synthesis of functionalized dihydropyranones
from simple starting materials. The molecular sieves played a
crucial role in the yield and selectivity. The mild conditions
and high enantioselectivities make this approach quite attractive.
The reactions starting from ynals are atom-economical.
Furthermore the reactions of enals demonstrated broader
substrate compatibility. Efforts aimed at further investigation
of the chiral NHC-catalyzed reactions of a,b-unsaturated
aldehydes are currently underway.
Considering that the same acyl azolium intermediate was
involved in NHC-catalyzed reaction of ynals and enals,4–6
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 8670–8672 8671

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Table 3 NHC-catalyzed enantioselective annulation of enals with
1,3-dicarbonylsa
Angew. Chem., Int. Ed., 2007, 46, 2988; (d) D. Enders, O. Niemeier
and A. Henseler, Chem. Rev., 2007, 107, 5606; (e) V. Nair,
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For recent examples on NHC catalysis, see: (f) E. M. Phillips,
M. Wadamoto, A. Chan and K. A. Scheidt, Angew. Chem., Int.
Ed., 2007, 46, 3107; (g) M. He and J. W. Bode, J. Am. Chem. Soc.,
2008, 130, 418; (h) E. M. Phillips, T. E. Reynolds and
K. A. Scheidt, J. Am. Chem. Soc., 2008, 130, 2416; (i) A. Chan
and K. A. Scheidt, J. Am. Chem. Soc., 2008, 130, 2740;
(j) M. Rommel, T. Fukuzumi and J. W. Bode, J. Am. Chem.
Soc., 2008, 130, 17266; (k) S. P. Lathrop and T. Rovis, J. Am.
Chem. Soc., 2009, 131, 13628; (l) K. Hirano, A. T. Biju, I. Piel and
F. Glorius, J. Am. Chem. Soc., 2009, 131, 14190; (m) P.-L. Shao,
X.-Y. Chen and S. Ye, Angew. Chem., Int. Ed., 2009, 48, 192;
(n) T. Boddaert, Y. Coquerel and J. Rodriguez, Adv. Synth. Catal.,
2009, 351, 1744; (o) L. Gu and Y. Zhang, J. Am. Chem. Soc., 2010,
132, 914; (p) B. Cardinal-David, D. E. A. Raup and K. A. Scheidt,
J. Am. Chem. Soc., 2010, 132, 5345; (q) A. T. Biju, N. E. Wurz and
F. Glorius, J. Am. Chem. Soc., 2010, 132, 5970; (r) A. T. Biju and
F. Glorius, Angew. Chem., Int. Ed., 2010, 49, 9761.
2 R. Breslow, J. Am. Chem. Soc., 1958, 80, 3719.
3 K. Zeitler, Org. Lett., 2006, 8, 637.
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J. W. Bode, J. Am. Chem. Soc., 2010, 132, 8810;
(b) J. Mahatthananchai, P. Zheng and J. W. Bode, Angew. Chem.,
Int. Ed., 2011, 50, 1673.
5 Z.-Q. Zhu and J.-C. Xiao, Adv. Synth. Catal., 2010, 352, 2455.
6 (a) B. E. Maki, A. Chan, E. M. Phillips and K. A. Scheidt, Org.
Lett., 2007, 9, 371; (b) S. De Sarkar and A. Studer, Angew. Chem.,
Int. Ed., 2010, 49, 9266.
7 S. J. Ryan, L. Candish and D. W. Lupton, J. Am. Chem. Soc.,
2009, 131, 14176.
8 (a) D. Rosenthal, P. Grabowich, E. F. Sabo and J. Fried, J. Am.
Chem. Soc., 1963, 85, 3971; (b) A. K. Mandal and D. G. Jawalkar,
Tetrahedron Lett., 1986, 27, 99; (c) T. Kume, H. Iwasaki,
Y. Yamamoto and K. Akiba, Tetrahedron Lett., 1988, 29, 3825;
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2, 1097; (i) L. Candish and D. W. Lupton, Org. Lett., 2010,
12, 4836.
9 For NHC-catalyzed approaches to 3,4-dihydropyranones, see:
(a) M. He, G. J. Uc and J. W. Bode, J. Am. Chem. Soc., 2006,
128, 15088; (b) M. He, B. J. Beahm and J. W. Bode, Org. Lett.,
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2009, 11, 1623. For other approaches to 3,4-dihydropyranones not
using NHCs, see: (d) K. Itoh, M. Hasegawa, J. Tanaka and
S. Kanemasa, Org. Lett., 2005, 7, 979; (e) D. A. Evans,
R. J. Thomson and F. Francisco, J. Am. Chem. Soc., 2005,
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T. Mukaiyama, Chem.–Asian J., 2007, 2, 123; (g) Y. Li, Z. Yu
and H. Alper, Org. Lett., 2007, 9, 1647.
Entry
R
R1, R2
t/h Yieldb (%) Eec (%)
1
Ph
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OEt
Me, OEt
10
66
24
16
18
48
12
12
12
12
12
12
12
24
16
66
83 (3a)
73 (3b)
77 (3c)
87 (3d)
81 (3e)
74 (3f)
85 (3g)
73 (3h)
77 (3i)
37 (3q)
42 (3r)
67 (3s)
72 (3t)
56 (3u)
84 (3k)
81 (3v)
81 (3n)
72 (3w)
66 (3v)
58 (3o)
60 (3p)
90 (3y)
98
91
92
97
97
92
97
95
97
96
93
98
96
97
97
83
94
95
92
95
90
90
2d,e
3
4-OMeC6H4
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-FC6H4
4
5
6e
7
2-FC6H4
8
9
4-ClC6H4
4-BrC6H4
4-CNC6H4
4-CF3C6H4
4-CO2MeC6H4
10
11
12
13
14
15
16e
17
18
19
20
21
22
4-COCH3C6H4 Me, OEt
3-NO2C6H4
Me, OEt
Me, OEt
Me, OEt
2-Thienyl
Me
Ph
Ph
Ph
Ph
Ph
Ph
Me, OMe 12
Et, OEt
Ph, OEt
Me, Me
Me, Ph
Ph, Ph
22
24
22
24
24
a
Performed on a 0.3 mmol scale with 1.5 equiv. of 4, 1 equiv. of 2,
1 equiv. of [O], 10 mol% of C3, and 300 mg of 4 A MS in 0.1 M in
b
c
toluene at 40 1C. Isolated yield after chromatography. Determined
by HPLC analysis on a chiral column. 1 equiv. of aldehyde and
e
1.5 equiv. of 3-oxobutanoate were used. At room temperature.
d
We thank the Chinese Academy of Sciences (Hundreds of
Talents Program) and the National Natural Science Foundation
(20972179, 21032006) for financial support.
Notes and references
1 For recent reviews, see: (a) D. Enders and T. Balensiefer, Acc.
Chem. Res., 2004, 37, 534; (b) K. Zeitler, Angew. Chem., Int. Ed.,
2005, 44, 7506; (c) N. Marion, S. Dıez-Gonzalez and S. P. Nolan,
´ ´
10 For an earlier example on azolium salt as precatalysts without
addition of base, see: E. Ciganek, Synthesis, 1995, 1311–1314.
c
8672 Chem. Commun., 2011, 47, 8670–8672
This journal is The Royal Society of Chemistry 2011